Project Summary/Abstract Ionizing irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. These cognitive changes are particularly severe in individuals who were treated with radiation during childhood. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender . The neurobiological reason for this difference is unknown, and very few experimental studies have addressed this issue. Ionizing radiation in rodents has been consistently shown to activate several neuroinflammatory signaling cascades that can impact multiple neural processes and synaptic transmission, ultimately disrupting hippocampal function. Neuroinflammation, characterized by activation of brain resident microglia and recruitment of peripherally derived monocytes (collectively referred to as `myeloid cells'), has been consistently associated with the loss of cognitive function in mice after radiation. There are still no treatments for preventing or treating radiation-induced cognitive dysfunction. Despite the extensive clinical evidence linking fractionated brain irradiation with cognitive deficits, there are still unanswered gaps in the biologic basis of this observation: the mechanism/s by which activation of the inflammatory response affect cognitive function, and the effect of age and sex. Furthermore, there are no pre-clinical models that recapitulate the features of the most common clinical scenario: patients with central nervous system (CNS) tumors. Our final therapeutic goal is to prevent and treat the cognitive changes observed after fractionated whole-brain irradiation (fWBI) injury. We hypothesize that changes in the composition and function of myeloid cells following brain irradiation can both prevent and rescue cognitive deficits through durable effects on synapses. The translational objective of this proposal is to demonstrate that resetting the immune system by brief microglia depletion prevents the long-term development of memory deficits in a brain tumor model designed to mimic conventional treatment paradigms used in clinical settings. The specific aims in support of our hypothesis are: 1. Establish the effects of fWBI on memory and synaptic composition as a function of age and sex in an immunocompetent mouse glioma model. 2. Determine the role of myeloid cells in the development of fWBI-induced memory deficits. 3. Evaluate the role of myeloid cells as a mechanistic driver of the permanent memory deficits after fWBI. Very little is known in regard to the evolution of radiation induced pathophysiology in the context of peripherally derived macrophage accumulation or inflammation, and how this relates to altered synaptic and cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.